1. Technical Field
The present invention relates to novel compounds which inhibit the KCa3.1 and their use as medicaments.
2. Background Information
KCa3.1, also known as KCNN4, SK4, IKCa1, IK1 and Gardos channel, is an intermediate-conductance potassium-ion channel which is activated by intracellular calcium (1). The C-terminal calmodulin domain of KCa3.1 serves as a sensor for intracellular [Ca2+] and regulates Ca2+-mediated channel opening via cross-linking of subunits in the channel tetramer (2). Activation of KCa3.1 by elevated intracellular Ca2+ maintains a negative membrane potential through efflux of K+, which helps to sustain Ca2+ entry into the cell. KCa3.1 is expressed in a variety of cell types including T cell, B cell, macrophage, microglial cell, mast cell, red blood cell, fibroblast, vascular smooth muscle cell and epithelial cell. Thus, KCa3.1 plays an important function in regulating Ca2+ influx—mediated functions such as cytokine production, proliferation and migration in these cells. In T cells, sustained Ca2+ influx via the CRAC channel is important for sufficient cytokine production and proliferation. T-cell receptor engagement dramatically induces KCa3.1 expression, in parallel with increased KCa3.1 currents and enhanced [Ca2+]i signaling during human T-cell activation (3). KCa3.1 deficiency leads to decreased TCR-stimulated Ca2+ influx and cytokine production in mouse Th0, Th1, and Th2 cells (7). KCa3.1−/− mice are protected from developing severe colitis in two models of inflammatory bowel disease (IBD) (4), suggesting that KCa3.1 inhibitors could be beneficial for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In addition to IBD, KCa3.1 is also a potential target for several other disease indications including atherosclerosis, multiple sclerosis, rheumatoid arthritis, asthma, renal fibrosis, diabetes and sickle cell anemia. KCa3.1 inhibitors TRAM-34 and clotrimazole significantly reduces the development of atherosclerosis in aortas of ApoE−/− mice (5). TRAM-34 also inhibits in an experimental autoimmune encephalomyelitis (EAE) model induced by MOG35-55 peptide in C57BL/6 mice (6). KCa3.1 deficient mice show improved glucose homeostasis (through pancreatic beta cells) without affecting insulin sensitivity, suggesting KCa3.1 is a potential target for type II diabetes (7). In addition, KCa3.1 plays an important role in proliferation of renal fibroblasts, and KCa3.1 deficient mice or TRAM-34 treated mice show attenuated progression of renal fibrosis induced by unilateral ureteral obstruction (UUO) (7), indicating that KCA3.1 may serve as a therapeutic target for fibrotic kidney disease. Pharmacological KCa3.1 blockade reduced erythrocyte dehydration in both a mouse model of sickle-cell anemia and in patients with the disease (8). Taken together, a KCa3.1 inhibitor potentially will have therapeutic values for multiple disease indications.